1. Field of the Invention
This application is in the field of medicinal chemistry. The application relates to novel 1,3-dioxanomorphides and 1,3-dioxanocodides, and pharmaceutical compositions comprising any of these compounds. The application also relates to methods of making 1,3-dioxanomorphides and 1,3-dioxanocodides, and their use.
2. Description of the Related Art
Pain is the most common symptom for which patients seek medical advice and treatment. While acute pain is usually self-limited, chronic pain can persist for 3 months or longer and lead to significant changes in a patient's personality, lifestyle, functional ability and overall quality of life (K. M. Foley, Pain, in Cecil Textbook of Medicine 100-107, J. C. Bennett and F. Plum eds., 20th ed. 1996).
Pain has traditionally been managed by administering either a non-opioid analgesic (such as acetylsalicylic acid, choline magnesium trisalicylate, acetaminophen, ibuprofen, fenoprofen, diflunisal or naproxen), or an opioid analgesic (such as morphine, hydromorphone, methadone, levorphanol, fentanyl, oxycodone, oxymorphone, or buprenorphine).
Until recently, there was evidence of three major classes of opioid receptors in the central nervous system (CNS), with each class having subtype receptors. These receptor classes are known as μ, δ and κ. As opiates have a high affinity to these receptors while not being endogenous to the body, research followed in order to identify and isolate the endogenous ligands to these receptors. These ligands were identified as endorphins, enkephalins, and dynorphins, respectively. Additional experimentation has led to the identification of the opioid receptor-like (ORL-1) receptor, which has a high degree of homology to the known opioid receptor classes. This newly discovered receptor was classified as an opioid receptor based only on structural grounds, as the receptor did not exhibit pharmacological homology. It was initially demonstrated that non-selective ligands having a high affinity for μ, δ and κ receptors had low affinity for the ORL-1 receptor. This characteristic, along with the fact that an endogenous ligand had not yet been discovered, led to the ORL-1 receptor being designated as an “orphan receptor”.
Buprenorphine, (2S)-2-[17-cyclopropylmethyl-4,5α-epoxy-3-hydroxy-6-methoxy-6α,14α-ethanomorphinan-7α-yl]-3,3-dimethylbutan-2-ol, a semi-synthetic opioid having the structure:
is used to treat opioid addiction, to control moderate acute pain in non-opioid tolerant individuals, and to control moderate chronic pain. Buprenorphine is classified both as an orvinol and as a thevinol, which means that it can be derived from either oripavine or thebaine. K. W. Bentley discovered buprenorphine using thebaine as the initial backbone structure. Thebaine is one of the main alkaloids in the Iranian poppy (Papaver bracteatum). Thebaine can also be isolated from Papaver somniferum which is also a source for oripavine (U.S. Pat. No. 6,723,894).
Buprenorphine has an extremely high binding affinity at the μ- and κ-opioid receptors. It has partial agonist activity at the μ-opioid receptor, partial or full agonist activity at the ORL-1/nociceptin and δ-opioid receptors, and competitive antagonist activity at the κ-opioid receptor. Buprenorphine exhibits an analgesic effect approximately 25 to 40 times more potent than morphine (by weight of equivalent low doses). Buprenorphine is marketed as oral formulations (tablets, sublingual tablets, and sublingual films), parenteral preparations, and transdermal patches.
Buprenorphine differs from the majority of morphinane alkaloids by the presence of an additional 6,14-ethano bridge and a carbinol (tertiary alcohol) in the side-chain. This tertiary alcohol gives rise to an acid catalyzed decomposition of buprenorphine, which, depending on the conditions, either results in dehydration and formation of EP Impurity F (compound 2 in Garrett, E. R., et al., Journal of Pharmaceutical Sciences 74:515-523 (1985)) or in rearrangement with the loss of methanol and formation of a furanomorphide (demethoxy-buprenorphine, EP Impurity I) (compound I in Cone, E. J. et al., Journal of Pharmaceutical Sciences 73:243-246 (1984) and compound 3 in Garrett, E. R., et al., supra). EP Impurity I has been further studied with other ring constrained furanomorphides (Husbands, S. M., et al., Bioorganic & Medical Chemistry Letters 9:831-834 (1999); {hacek over (C)}ejka, J., et al., Acta Cryst. E61:2274-2276 (2005)).
There is a need for buprenorphine derivatives that have a decreased sensibility towards acids while maintaining the pharmacological activity.